Selective estrogen receptor modulators (SERMs) are synthetic compounds that bind to genomic estrogen receptors (ER), mimicking estrogen in some tissues, and antagonizing it in others. The SERM raloxifene antagonizes estrogen in both the breast and uterus, conferring a degree of protection against breast and uterine cancers, while it serves as an estrogen agonist in lipid and bone metabolism, providing some protection against both osteoporosis and heart disease. In 1997, the U.S. FDA approved the use of raloxifene for the prevention of osteoporosis. As a result, raloxifene will soon be used by millions of postmenopausal women. There is a large and rapidly growing literature concerning the effects of b-estradiol on the brain, both on brain function generally (maintenance of cognitive abilities and protection against Alzheimer's disease) and on individual neurons (promotion of neurite outgrowth and dendritic spine production, nitric oxide synthase activation, and neuroprotection). A major gap in the current understanding of raloxifene is how it influences the brain. We will use cultured rat hippocampal and cortical neurons to accomplish the following aims: 1. To test the hypothesis that raloxifene will either mimic or antagonize the neuroprotective effects of b-estradiol against oxidative stress in vitro. 2. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on calcium levels in neurons. 3. To test the hypothesis that raloxifene will either reduce or enhance calmodulin activation. The SERM tamoxifen reduces calmodulin activity, suggesting that raloxifene should also be tested for this property. 4. To test the hypothesis that raloxifene will mimic or antagonize the effects of b-estradiol on nitric oxide synthase. The production of NO, which has been implicated in several aspects of neuronal differentiation and learning, is enhanced by b-estradiol. This enhancement is blocked by the SERM tamoxifen.